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TRAIL induces apoptosis but not necroptosis in colorectal and pancreatic cancer cells preferentially via the TRAIL-R2/DR5 receptor
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SYSNO ASEP 0503426 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title TRAIL induces apoptosis but not necroptosis in colorectal and pancreatic cancer cells preferentially via the TRAIL-R2/DR5 receptor Author(s) Nahácka, Zuzana (UMG-J)
Švadlenka, Jan (UMG-J)
Peterka, Martin (UMG-J)
Ksandrova, Marie (UMG-J)
Benešová, Simona (UMG-J)
Neuzil, J. (AU)
Anděra, Ladislav (UMG-J) RIDNumber of authors 7 Source Title Biochimica Et Biophysica Acta-Molecular Cell Research. - : Elsevier - ISSN 0167-4889
Roč. 1865, č. 3 (2018), s. 522-531Number of pages 10 s. Language eng - English Country NL - Netherlands Keywords trail ; Apoptosis ; Necroptosis ; Receptor-specific signaling ; Cancer Subject RIV EB - Genetics ; Molecular Biology OECD category Biochemistry and molecular biology R&D Projects LH12202 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) GA15-03379S GA ČR - Czech Science Foundation (CSF) GA15-14789S GA ČR - Czech Science Foundation (CSF) ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Institutional support UMG-J - RVO:68378050 UT WOS 000430755300006 DOI 10.1016/j.bbamcr.2017.12.006 Annotation Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine that can trigger apoptosis in many types of human cancer cells via engagement of its two pro-apoptotic receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). TRAIL can also activate several other signaling pathways such as activation of stress kinases, canonical NF-KB signaling and necroptosis. Though both receptors are ubiquitously expressed, their relative participation in TRAIL-induced signaling is still largely unknown. To analyze TRAIL receptor-specific signaling, we prepared Strep-tagged, trimerized variants of recombinant human TRAIL with high affinity for either DR4 or DR5 receptor. Using these receptor-specific ligands, we examined the contribution of individual pro-apoptotic receptors to TRAIL-induced signaling pathways. We found that in TRAIL-resistant colorectal HT-29 cells but not in pancreatic PANC-1 cancer cells, DISC formation and initial caspase-8 processing proceeds comparably via both DR4-and DR5-activated signaling. TRAIL-induced apoptosis, enhanced by the inhibitor of the Bcl-2 family ABT-737, or by the translation inhibitor homoharringtonine, proceeded in both cell lines predominantly via the DR5 receptor. ShRNA-mediated downregulation of DR4 or DR5 receptors in HT-29 cells also pointed to a stronger contribution of DR5 in TRAIL-induced apoptosis. In contrast to apoptosis, necroptotic signaling was activated similarly by both DR4- or DR5-specific ligands. Activation of auxiliary signaling pathways involving NF-xB or stress kinases proceeded under apoptotic conditions mainly in a DR5-dependent manner, while these signaling pathways were during necroptosis similarly activated by either of these ligands. Our study provides the first systematic insight into DR4 /DR5-specific signaling in colorectal and pancreatic cancer cells. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2019
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